Mika Hori1, Naotaka Ohta2, Atsushi Takahashi3, Hiroaki Masuda2, Rieko Isoda2, Suguru Yamamoto2, Cheol Son2, Masatsune Ogura4, Kiminori Hosoda2, Yoshihiro Miyamoto2, Mariko Harada-Shiba5. 1. Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe Shinmachi, Suita, Osaka, 564-8565, Japan. Electronic address: mihori@ncvc.go.jp. 2. Laboratory of Clinical Genetics, National Cerebral and Cardiovascular Center, 6-1 Kishibe Shinmachi, Suita, Osaka, 564-8565, Japan. 3. Department of Genomic Medicine, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe Shinmachi, Suita, Osaka, 564-8565, Japan. 4. Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe Shinmachi, Suita, Osaka, 564-8565, Japan. 5. Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe Shinmachi, Suita, Osaka, 564-8565, Japan. Electronic address: mshiba@ncvc.go.jp.
Abstract
BACKGROUND AND AIMS: More than 4970 variants in the low-density lipoprotein receptor (LDLR) gene and 350 variants in the proprotein convertase subtilisin/kexin 9 (PCSK9) gene have been reported in familial hypercholesterolemia (FH) patients. However, the effects of these variants on FH pathophysiology have not been fully clarified. We aimed to update the LDLR and PCSK9 variants in Japanese heterozygous FH (HeFH) patients and annotate their clinical significance for the genetic diagnosis of HeFH. METHODS: A genetic analysis of the LDLR and PCSK9 genes was performed in 801 clinically diagnosed HeFH patients. The association of the pathogenic variants with the clinical FH phenotype was examined. RESULTS: Pathogenic variants in the LDLR and PCSK9 genes were found in 46% (n = 296) and 7.8% (n = 51) of unrelated FH patients (n = 650), respectively. The prevalence of Achilles tendon thickness was low (44%) in patients harbouring PCSK9 pathogenic variants. Furthermore, 17% of unrelated FH patients harboured one of five frequent LDLR pathogenic variants: c.1845+2T > C, c.1012T > A: p.(Cys338Ser), c.1297G > C: p.(Asp433His), c.1702C > G: p.(Leu568Val), and c.2431A > T: p.(Lys811*). Patients harbouring the c.1845+2T > C and c.1702C > G: p.(Leu568Val) variants had significantly lower serum LDL-cholesterol levels and higher serum HDL-cholesterol levels, respectively, compared with those harbouring the other LDLR pathogenic variants. The proportion of LDLR pathogenic variants was higher in patients with a younger age of coronary artery disease (CAD) onset and significantly decreased as the age of CAD onset increased. CONCLUSIONS: This study annotated the clinical significance and characteristics of LDLR and PCSK9 pathogenic variants in Japanese HeFH patients.
BACKGROUND AND AIMS: More than 4970 variants in the low-density lipoprotein receptor (LDLR) gene and 350 variants in the proprotein convertase subtilisin/kexin 9 (PCSK9) gene have been reported in familial hypercholesterolemia (FH) patients. However, the effects of these variants on FH pathophysiology have not been fully clarified. We aimed to update the LDLR and PCSK9 variants in Japanese heterozygous FH (HeFH) patients and annotate their clinical significance for the genetic diagnosis of HeFH. METHODS: A genetic analysis of the LDLR and PCSK9 genes was performed in 801 clinically diagnosed HeFH patients. The association of the pathogenic variants with the clinical FH phenotype was examined. RESULTS: Pathogenic variants in the LDLR and PCSK9 genes were found in 46% (n = 296) and 7.8% (n = 51) of unrelated FHpatients (n = 650), respectively. The prevalence of Achilles tendon thickness was low (44%) in patients harbouring PCSK9 pathogenic variants. Furthermore, 17% of unrelated FHpatients harboured one of five frequent LDLR pathogenic variants: c.1845+2T > C, c.1012T > A: p.(Cys338Ser), c.1297G > C: p.(Asp433His), c.1702C > G: p.(Leu568Val), and c.2431A > T: p.(Lys811*). Patients harbouring the c.1845+2T > C and c.1702C > G: p.(Leu568Val) variants had significantly lower serum LDL-cholesterol levels and higher serum HDL-cholesterol levels, respectively, compared with those harbouring the other LDLR pathogenic variants. The proportion of LDLR pathogenic variants was higher in patients with a younger age of coronary artery disease (CAD) onset and significantly decreased as the age of CAD onset increased. CONCLUSIONS: This study annotated the clinical significance and characteristics of LDLR and PCSK9 pathogenic variants in Japanese HeFH patients.